Antimicrobial fibres

ABSTRACT

Described is a method of manufacturing carboxymethyl cellulose (CMC) fibres containing an antimicrobial, the fibres being suitable for use in the preparation of wound dressings, wherein the antimicrobial is selected from the group consisting of a biguanide, a biguanide derivative, octenidine, taurolidine, and a combination of two or more thereof, the method comprising, submerging CMC fibres comprising at least 95 wt % carboxymethylcellulose on a dry weight basis in a treatment solution for a duration adequate to provide the CMC fibres containing an antimicrobial, the treatment solution comprising the antimicrobial and at least 70 wt % of a water-miscible organic solvent selected from C1-C4 alkanols, C3-C5 ketones, and a combination of two or more thereof. Anti-microbial CMC fibres obtained by the methods and wound dressings containing such fibres are also described.

The present invention relates to a method of manufacturingcarboxymethylcellulose (CMC) fibres containing an antimicrobial agentfor use in wound dressings, particularly carboxymethylcellulose fibrescomprising polyhexamethylene biguanide (PHMB). Anti-microbial CMC fibresobtainable by such methods are described, as are wound dressingscontaining such fibres. The present invention is particularly relevantto the manufacture of fibrous non-woven components of wound dressings.

BACKGROUND

Wound dressings are widely used to assist in the healing process ofwounds. Wounds may vary in severity, from grazes to cuts, to deep woundscaused by trauma or surgery. It is generally desirable that wounddressings are flexible so that the medical practitioner can adapt thewound dressing to be in conformity with the profile of the wound.Moreover, flexibility in the wound dressing allows the patient to movemore freely, without causing undesirable damage to the wound and thehealing tissue. It is also desirable that wound dressings have a softfeel, to provide comfort for the patient and to reduce damage to thewound and/or pain caused by the dressing.

Some wounds, particularly chronic wounds caused by trauma or surgery,excrete a liquid exudate comprising mainly water along with salts,proteins for assisting in the healing process, as well as cells such aswhite blood cells. During the healing process, it is desired that thewound be kept moist to help in the healing process, but not too moist asthis may increase the risk of infection and impair healing. It istherefore desirable that wound dressings also be absorbent.

Wound dressings comprising gelling fibres are known, owing to theirability to absorb wound exudate whilst maintaining a desirable moistenvironment for wound healing and a conformable wound contact surface.Upon absorption of water from the wound exudate, the gelling fibresundergo an irreversible gelling process. Wound dressings comprisinggelling fibres can promote granulation tissue and assist in healing. Thedressing may, for example, be in the form of a non-woven felt. Whenwound dressings made from gelling fibres are applied to a wound (suchapplication often being in conjunction with a secondary dressing such asa breathable film that overlies the fibrous dressing) exudate from thewound is absorbed by the dressing, which results in the dressingconverting it into the form of a gel. Such gels are advantageous inwound care because they maintain an ideal moist wound environment and“lock-in” the wound exudate that has been absorbed. The fibres used forproducing the wound dressing generally produce a gel of sufficientintegrity so as not to disintegrate within the wound, at least withinthe time for which the dressing is intended to remain in place, so thedressing may be removed intact from the wound.

Carboxymethylcellulose (CMC) has been commonly employed as a gellingpolymer in the preparation of wound dressings due to its desirablephysical and chemical properties in the context of wound careapplications. CMC fibres for use in wound dressings are conventionallyprepared by carboxymethylation of pre-prepared cellulose fibres(cellulose fibres are also known as viscose or rayon). This approach(i.e. carboxymethylation of a pre-prepared fibre) is adopted because CMCin powder form is not capable of forming fibres by conventionalprocesses such as spinning. Thus, it is necessary to pre-prepare fibres(of a fibre-forming material such as cellulose) that can becarboxymethylated. Thus, for example, EP0616650 discloses a process inwhich solvent-spun cellulose fibre is carboxymethylated by reaction witha solution containing a strong alkali (e.g. sodium hydroxide) and amonochloroacetate reagent (e.g. sodium chloroacetate). The degree ofsubstitution is controlled by the concentration of the components in thereaction solution and the processing conditions.

The inability of CMC powder per se to be fibre-forming is in contrast tocoagulating polymers like alginates, which readily form fibres byconventional fibre forming techniques (such as by spinning an aqueoussolution (“dope”) of a soluble form of the alginate (e.g. the sodiumsalt) through a spinneret into a coagulation bath containingmulti-valent cations (usually calcium) that cross-link the alginate toform fibres).

CMC fibres per se have been used as a wound-contacting surface in wounddressings, as described in WO9416746. Wound dressings have been proposedcontaining CMC fibres and alginate fibres. For example, EP0783605describes wound dressings comprising CMC fibres and alginate fibres.Wound dressings have also been disclosed containing fibres comprisingCMC co-spun with alginate, to form fibres that each contain a homogenousmixture of CMC and alginate. Processes for co-spinning alginate and CMCto form fibres containing a mixture of both materials are for instancedescribed in WO2017/085436.

It is well known to include anti-microbial agents in wound dressings toreduce infection during use. When anti-microbials are included, it isdesirable to achieve a suitable loading in the dressing and for theanti-microbial to be releasable at a suitable rate. In this regard, itis desirable that the dressing elute at least some of anti-microbial toallow the anti-microbial effect to be observed at the site of the wound.Different fibre polymer/anti-microbial combinations will demonstratedifferent loading/elution properties. The incorporation ofanti-microbial agents into a dressing can however have an impact on theprocessability of the wound dressings/polymer fibres and may, in somecases, lead to less desirable physical properties (e.g. stiffness)relative to wound dressings provided without the anti-microbial agent.

For instance, for some wound dressing polymer materials, anti-microbialagents may be readily incorporated into the fibre polymer during theinitial fibre-forming step. This is, for instance, possible in the caseof alginate fibres. Alginate fibres for wound dressings are typicallyprepared by a wet-spinning process whereby a soluble alginate iscontacted with a calcium salt to cause crosslinking, thereby causing thefibre polymer to coagulate into fibres, as described above. During suchprocesses, anti-microbial compounds may be either dissolved or suspendedin the polymer solution (“dope”) to be incorporated into the resultingcoagulated fibres in situ.

Such methods are not, however, suitable for CMC fibres, which are notproducible by the sort of spinning methods described above foralginates. As already described above, CMC fibres for use in wounddressings are usually prepared by functionalisation (carboxymethylation)of pre-formed cellulose fibres. This is usually by treating thecellulose with a carboxymethylating treatment composition, followed bywashing steps, to remove unreacted reagent, by-products, and any excesswater. As such, the manufacture of CMC fibres typically based onmodification of a pre-existing fibre, not by coagulation of a new fibreas in the case of alginates or similarly coagulatable polymers.

In view of this, it is conventional for anti-microbial agents to beapplied to CMC fibres only after formation of the CMC fibres has takenplace, which can produce a number of drawbacks, particularly when highlywater-soluble anti-microbial agents such as polyhexamethylene biguanide(PHMB) are sought to be used.

PHMB is an anti-microbial agent having particular utility in the fieldof wound dressings. It is a highly water-soluble compound, and exhibitspoor solubility in organic solvents. As such, prior art methods forapplying PHMB to CMC wound dressings generally rely on application of anaqueous solution of PHMB following formation of the wound dressing. Anexample of such a method of applying an aqueous solution of PHMB to afibrous non-woven CMC wound dressing is described in CN102462860,whereby the pre-formed non-woven wound dressing is sprayed with anaqueous solution of PHMB. This method, however, has a number ofdrawbacks. Firstly, spraying the final formed wound dressing results inonly the outer surface of the fibrous dressing being coated with PHMB.In essence, this means that the distribution of PHMB is highly localisedto the wound dressing surface. Whilst this may allow the anti-microbialto contact the wound, it would not prevent microbes from growing withinthe deeper body of the wound dressing, where such microbes may thenpotentially re-infect the wound. Moreover, such spraying methods aremore prone to the aqueous solution of PHMB being applied in anon-uniform manner, which may result in areas of relatively high PHMBconcentration and areas of relatively low PHMB concentration on thewound-dressing surface. Additionally, and importantly, CMC fibresundergo a gelling process upon contact with water. Known methods ofapplying PHMB to CMC fibres/wound dressings using aqueous solutions aretherefore prone to causing premature gelation of the CMC fibres. Oncefibres have been caused to gel and then are allowed to dry (even if onlyhaving gelled in part), the resulting fibres are more brittle andexperience diminished softness/conformability (increased stiffness)compared to CMC fibres provided without the anti-microbial treatment.This change in physical properties is irreversible. These areundesirable properties for a patient and will not only diminish patientcomfort (which may therefore decrease patient compliance) but may alsolead to reduced conformity to the wound, and a less desirable woundenvironment for healing.

It is an object of the present invention to mitigate or obviate one ormore of the problems identified above.

It is for instance desirable to provide anti-microbial CMC fibres/wounddressings containing such fibres, which retain a desirableconformability and softness; and/or to provide wound dressingscontaining anti-microbial agent throughout the fibrous wound dressing;and/or which achieve desirable loading of anti-microbial agent into CMCfibres and/or elution from CMC fibres.

SUMMARY OF INVENTION

At its most general, the present invention provides new and advantageousmethods of preparing antimicrobial CMC fibres for wound dressingapplications, as well as providing resulting anti-microbial CMC fibresand wound dressings comprising such CMC fibres. Advantageously, thepresent invention obviates issues associated with applying aqueousantimicrobial solutions directly to CMC wound dressings, as isconventional in the art.

The inventors have in particular developed a method wherebywater-soluble organic anti-microbial agents such as PHMB can beincorporated into CMC fibres for wound dressings in adequate loadingsand whilst applying the anti-microbial evenly to the fibre, but withoutexperiencing the reduction in conformability and softness associatedwith aqueous treatment methods described in the prior art. Inparticular, it was surprisingly observed by the inventors that byutilising a treatment solution containing PHMB and at least 70 wt %organic solvent, PHMB was loaded into CMC fibres in adequate quantitiesbut without any observed gelation of the CMC fibre polymer, thus leadingto more conformable fibres and dressings.

Moreover, by virtue of the methods proposed herein, CMC fibres areevenly exposed to the anti-microbial agent, allowing for a consistentantimicrobial release profile across the fibre length. The disclosurethus contemplates use of the resulting fibres in the manufacture offibrous wound dressings, e.g. non-wovens also advantageously producesfibrous articles for wound dressings, or dressings themselves, whereinthe antimicrobial agent may be distributed throughout thearticle/dressing. This has the advantage that the anti-microbial effectmay not only be provided at the wound contact surface, but also withinthe entire body of the dressing to prevent microbes from growing withinthe dressing, thus reducing the chance of reinfection of the wound.Additionally, because of the convenient nature of the treatment step ofthe invention, the present methods of the invention can be readilyincorporated as a step (e.g. a wash step) in the manufacturing processof CMC fibres, as is evident in embodiments described herein. Thepresent methods also therefore provide versatility and efficiency,obviating the need for applying anti-microbials after manufacture of thewound dressing, such as described in CN102462860, referenced above.

According to a first aspect of the present invention, there is provideda method of manufacturing carboxymethylcellulose (CMC) fibres containingan antimicrobial, the fibres being suitable for use in the preparationof wound dressings, wherein the antimicrobial is selected from the groupconsisting of a biguanide, a biguanide derivative, octenidine,taurolidine, and a combination of two or more thereof, the methodcomprising:

-   -   submerging CMC fibres comprising at least 95 wt %        carboxymethylcellulose by dry weight basis in a treatment        solution, the treatment solution comprising:        -   a) the antimicrobial, optionally in an amount of from 1-10            wt %; and        -   b) at least 70 wt % of a water-miscible organic solvent            selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a            combination of two or more thereof;    -   for a duration adequate to provide the CMC fibres containing the        antimicrobial.

This method advantageously allows water-soluble organic anti-microbialagents such as PHMB to be incorporated into CMC fibres for wounddressings in adequate loadings and whilst applying the anti-microbialevenly to the fibre. This is without experiencing the reduction inconformability and softness associated with aqueous treatment methodsdescribed in the prior art. By utilising a treatment solution containingthe anti-microbial and at least 70 wt % organic solvent, PHMB was loadedinto CMC fibres in adequate quantities but without any observed gelationof the CMC fibre polymer.

Advantageously, in accordance with the present invention, the method isable to produce carboxymethylcellulose (CMC) fibres containing anantimicrobial prior to incorporation of the fibres into an article, e.g.a woven or non-woven article, or dressing containing such article. Intypical embodiments, the method does not include submerging fibres otherthan the CMC fibres comprising at least 95 wt % carboxymethylcelluloseby dry weight basis in the treatment solution as described above. Inother words, the CMC fibres described may be the sole fibres submergedaccording to the method.

The treatment solution may comprise from 1-10 wt % of the antimicrobial;and at least 70 wt % of a water-miscible organic solvent relative to thetotal weight of the treatment solution. The high wt % of organic solventadvantageously prevents the CMC fibres from prematurely gelling butsimultaneously allows delivery of the anti-microbial. The presentinvention therefore advantageously allows an antimicrobial to bedelivered to the CMC fibres, whilst avoiding undesirable andirreversible premature gelling of the CMC fibres, which can lead tobrittleness and stiffness, as described above.

Without wishing to be bound by theory, it is believed that the solventin the treatment solution causes swelling of the CMC polymer fibrewithout gelling, thus allowing the anti-microbial agent in the treatmentsolution to enter the polymer fibre matrix to provide adequate loadingand, in embodiments, an even distribution of anti-microbial within thefibre. Embodiments of CMC fibres prepared in accordance with the presentinvention are provided with an antimicrobial within the polymer matrix,and advantageously retain desirable conformability. Moreover, asdescribed in more detail below, the method according to the presentinvention may be readily and conveniently incorporated into themanufacturing process of the CMC fibres, e.g. from starting cellulose,thereby reducing waste solvent and increasing efficiency andproductivity.

Antimicrobials, such as biguanides (such as PHMB) and biguanidederivatives, generally have excellent solubility in water, but aretypically only sparingly soluble in organic solvents. For example, PHMBis very soluble in water (426 g/L), but has poor solubility in organicsolvents (10⁻³ g/L). For example, PHMB only exhibits solubility inethanol of up to 0.5 wt % at ambient temperature. It has beensurprisingly found that submerging CMC fibres in a treatment solutioncomprising a high organic solvent content and an antimicrobial selectedfrom those claimed, for example PHMB, nonetheless provides desirablefinal concentrations of antimicrobial in the CMC fibres containing theantimicrobial.

According to a second aspect of the present invention, there is provideda carboxymethylcellulose (CMC) fibre containing an antimicrobialselected from the group consisting of a biguanide, a biguanidederivative, octenidine, taurolidine, and a combination of two or morethereof, for use in the preparation of wound dressings, the CMC fibrebeing obtained or obtainable by a method according to the first aspectof the present invention.

As described above, such fibres contain adequate loading ofanti-microbial agent and advantageously exhibit improvedconformability/softness relative to anti-microbial CMC fibres that havebeen prepared by treatment of CMC fibres with aqueous anti-microbialcompositions.

According to a third aspect of the present invention, there is provideda carboxymethylcellulose (CMC) fibre containing an antimicrobialselected from a biguanide, a biguanide derivative, octenidine,taurolidine, and a combination of two or more thereof for use in thepreparation of wound dressings, wherein the antimicrobial is dispersedthroughout the fibre polymer. Without wishing to be bound by theory, itis believed that the solvent in the treatment solution causes swellingof the CMC polymer fibre, thus allowing the anti-microbial agent in thetreatment solution to enter the polymer fibre matrix, which inaccordance with this aspect of the invention, provides antimicrobialdispersed throughout the fibre polymer, e.g. evenly dispersed.

According to a fourth aspect of the present invention, there is provideda carboxymethylcellulose (CMC) fibre containing an antimicrobialselected from a biguanide, a biguanide derivative, octenidine,taurolidine, and a combination of two or more thereof for use in thepreparation of wound dressings, wherein the CMC fibre polymer has notundergone gelation. As described above, methods of the invention areadvantageously able to produce CMC fibres containing anti-microbialswhilst avoiding gelling of the CMC, by delivering the anti-microbial ina treatment solution containing high levels of organic solvents (andtherefore relatively low levels of water). This is in contrast tomethods of the prior art which use aqueous treatment methods to deliveranti-microbials such as PHMB to CMC fibres, thus leading to prematuregelling.

According to a fifth aspect of the present invention, there is provideda woven, non-woven or knitted material comprising CMC fibres containingan antimicrobial, wherein the CMC fibres containing an antimicrobial aredefined according to any one of the second, third or fourth aspects ofthe invention. The material is preferably a non-woven and mostpreferably a felt.

According to a sixth aspect of the present invention, there is provideda non-woven material (preferably a felt) comprising entangled CMC fibrescontaining an antimicrobial, wherein the antimicrobial is selected froma biguanide, a biguanide derivative, octenidine, taurolidine, and acombination of two or more thereof, wherein the non-woven materialexhibits a conformability characterised by an overhang length in thelongitudinal direction of up to 6.5 cm, as determined by the Cantilevermethod described in ASTM D1388-08. This Cantilever method and methods ofpreparing the non-woven for the Cantilever testing are described in moredetail herein in the examples section. Methods described hereinadvantageously allow production of CMC fibres containing ananti-microbial agent whilst avoiding premature gelation. This thereforeensures that the CMC fibres retain softness, enabling production ofresulting wound dressings that contain anti-microbial agent, but whichstill exhibit desirable conformability, as demonstrated by therelatively low overhang lengths recited, as determined by the Cantilevermethod.

According to a seventh aspect of the invention, there is provided awound dressing comprising CMC fibres containing an antimicrobial,wherein the CMC fibres containing an antimicrobial are defined accordingto any one of the second, third or fourth aspects of the invention. Thewound dressing may for instance contain a material according to thefifth or sixth aspects of the invention. The wound dressing may containthe material as the sole layer of the wound dressing, or typically, thewound dressing may be a multi-layer dressing wherein the material ispresent as a layer within the multi-layer dressing.

The aspects and embodiments of the present invention will now bedescribed in more detail by way of example only.

General Definitions

As referred to herein, “carboxymethyl cellulose (CMC)” refers tocellulose containing pendant carboxymethyl groups bound to some of thehydroxyl groups of the glucose monomers that make up the cellulosebackbone. Such carboxymethyl groups may typically be provided byreaction of cellulose starting material (such as rayon, e.g. viscose)with a carboxymethylating agent to cause carboxymethylation of freehydroxyl groups. In embodiments of the invention, the CMC (e.g. of theCMC fibres) is characterised by a degree of substitution of from 0.05 to0.8, typically 0.65, which is intended to mean that from 0.05 to 0.8carboxymethyl groups are provided per glucose unit, as determined bypotentiometric titration. Carboxymethyl groups will be understood to bea —CH₂COOH group, wherein the carboxymethyl group is bound to thecellulose backbone via a pendant hydroxyl group to form an ether bondi.e. —OCH₂COOH.

Unless expressly defined otherwise herein, the term“carboxymethylcellulose (CMC) fibre” is intended to refer to a fibreconsisting of, or consisting essentially of, CMC as the structural fibrepolymer, e.g. wherein the fibre-forming polymer component is at least 95wt % CMC, such as 96, 97, 98 or 99 wt % CMC. A CMC fibre according tothe present invention will therefore be substantially absent, or inembodiments entirely absent, of structural fibre polymers other thanCMC, e.g. wherein the fibre-forming polymer component contains less than5 wt %. of structural fibre polymers other than CMC, such as less than 4wt %, 3 wt %, 2 wt % or 1 wt % of structural fibre polymers other thanCMC. Examples of structural fibre polymers include those typically usedfor forming fibres in wound dressings and include alginates. Otherexamples will be readily apparent to the skilled person. Preferably, theCMC fibres are absent of alginate. It will however be appreciated thatminor amounts of undesired polymeric impurities, or other intendedpolymeric materials that do not form the structural fibre matrix itself(e.g. surfactants, spin finish agents, or other wound care additives)may be present, and such components are not intended to be excluded bythe term “CMC fibres” (e.g. wherein such additives may be encompassed byor otherwise contained within the fibre matrix, but are not part of thestructural matrix itself). Embodiments of CMC fibres according to theinvention may thus contain such additives, which may for instanceinclude surfactants and/or spin finish agents. Examples of spin finishagents are surfactants. A preferred example is polysorbate, e.g.polysorbate 20 (Tween).

Within the context of the present invention, the term “biguanide” refersto the class of anti-microbial compounds containing a biguanide moiety,including biguanides that contain pendant substituents such as one ormore C₁-C₈ alkyl groups, C₁-C₈ alkoxy groups, and/or an aryl-C₁₋₈alkylgroup, e.g. phenylethyl group. Such compounds may contain multiplebiguanide moieties and may for instance include biguanide polymers.

Well-known examples of biguanides include polyaminopropyl biguanide(PAPB), polyhexamethylene biguanide (PHMB), metmorfin(dimethylbiguanide), phenformin (phenethylbiguanide), propylbiguanide,buformin (butylbiguanide), hexylbiguanide, alexidine and chlorhexidine,with PHMB being particularly preferred.

Herein, the terms “antimicrobial”, and “antimicrobial agent” areintended to be equivalent and are used interchangeably.

The term “C₁-C₄ alkanol” refers to an alkane having from 1 to 4 carbonatoms wherein one or more hydrogens of the alkane are substituted with ahydroxyl group, typically with one hydroxyl group, i.e. the alkanols aretypically mono-ols, e.g. ethanol. It is contemplated that the C₁-C₄alkanol may include substitution wherein one or more hydrogen atoms ofthe alkane are each independently substituted with one or more groupsselected from amino (including primary, secondary and tertiary amino),C═O, and halo (e.g. F, Cl). Typically, the C₁-C₄ alkanol is notsubstituted, e.g. ethanol.

The term C₃-C₅ ketone refers to an alkane having from 1 to 3 carbonatoms, wherein at least one non-terminal carbon is a carbonyl (i.e.C═O). Typically, only one such carbonyl group is present, i.e. theketone is typically a monoketone, e.g. acetone. It is contemplated thatthe C₃-C₅ ketones may include substitution wherein one or more hydrogenatoms of the alkane backbone are each independently substituted with oneor more groups selected from amino (including primary, secondary andtertiary amino), OH, and halo (e.g. F, Cl). Typically, the ketones arenot substituted, e.g. acetone.

For avoidance of doubt, references herein to wt % amounts of componentsdescribed on a “dry weight basis” are intended to refer to the quantityof the given component in the material relative to the total solidscontent of the material as a whole, i.e. is intended to exclude the massof solvents such as water.

Herein, the term “gsm” means g/m². These two terms are usedinterchangeably.

DETAILED DESCRIPTION

According to the first aspect of the present invention, there isprovided a method of manufacturing carboxymethylcellulose (CMC) fibrescontaining an antimicrobial, the fibres being suitable for use in thepreparation of wound dressings, wherein the antimicrobial is selectedfrom the group consisting of a biguanide, a biguanide derivative,octenidine, taurolidine, and a combination of two or more thereof, themethod comprising:

-   -   submerging CMC fibres comprising at least 95 wt %        carboxymethylcellulose in a treatment solution, the treatment        solution comprising:        -   a) the antimicrobial, optionally in an amount of from 1-10            wt %; and        -   b) at least 70 wt % of a water-miscible organic solvent            selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a            combination of two or more thereof;    -   for a duration adequate to provide the CMC fibres containing the        antimicrobial.

Within the context of the present invention, submerging means to causeat least some length of the CMC fibres, and preferably the entire lengthof the CMC fibres to be surrounded by the treatment solution around theentire fibre circumference. This term is intended to encompass“soaking”, “dipping” or “wetting” of the CMC fibres into, or with, thetreatment solution. In a typical embodiment, the fibres are submerged ina bath containing the treatment solution. The fibres being submerged maytypically be continuous filament fibres. This method step may inprinciple be performed by pulling continuous filament fibres (e.g. inthe form of a fibrous “tow”) continuously through a treatment bath, suchas where only part of the fibre length at any one time is submerged inthe treatment solution, but wherein substantially all, or all of thefibre length is caused to be submerged in the treatment solution. Themethod is however preferably performed as a batch method by submergingentire fibre lengths (e.g. wherein the fibres are provided in the formof a tow) into a bath containing the treatment solution for an adequateduration. This has the advantage of evenly exposing the length of CMCfibres to the anti-microbial within the solution, which may thus inembodiments provide a generally even distribution of anti-microbialwithin the polymer. In such an embodiment, it will be appreciated thatit may be advantageous to secure (e.g. by tying) the ends of thefibres/tow to maintain the integrity of the fibres/tow. Without wishingto be bound by theory, it is also believed that submerging the fibres inthe treatment solution causes the fibre matrix to swell to permitpenetration of the anti-microbial into the CMC fibre polymer matrix,providing effective loading of the anti-microbial into the polymer.

The CMC fibres being submerged in the treatment solution, in accordancewith the first aspect of the present invention comprise at least 95 wt %CMC on a dry weight basis. In some embodiments, the CMC fibres compriseat least 96 wt %, 97 wt %, or 98 wt % CMC, optionally at least 99 wt %on a dry weight basis. In some embodiments, the CMC fibres that aresubmerged comprise 100% CMC on a dry weight basis. Preferably, the CMCfibres are entirely absent of any other fibre polymers. Preferably theCMC fibres are absent of alginates.

In embodiments, the CMC fibres submerged in the treatment solution arecontinuous fibres, also referred to in the art as continuous-filamentfibres. Those skilled in the art will understand thatcontinuous-filament fibres are long, continuous strands of fibres, whichmay be cut to a desired length. For example, CMC continuous-filament maybe provided in lengths of from 1-250 m. The upper end of this scale isindicative of large-scale manufacturing facilities capable of processingextremely long fibres/tows, for instance using large vessels. In someembodiments, the fibres are provided (e.g. cut) to a length of 2-7metres (m), optionally 3-6 m, optionally 4-5 m. In accordance with themethod of the present invention, the CMC fibres may be a length (e.g.cut length) of CMC continuous-filament secured at each end of the lengthto retain the structural integrity the CMC continuous-filament. Securingmay include tying-off the ends of the length of CMCcontinuous-filament/CMC fibres. In embodiments of the present invention,more than one CMC continuous-filament length is provided and submergedin the treatment solution. The CMC fibres may thus be provided as acontinuous-filament, e.g. in the form of a tow of CMC fibres. Theskilled artisan will appreciate that a “tow” refers to alongitudinally-parallel grouping of many continuous filament fibres,sometimes thousands of fibres, which can be conveniently transportedthrough fibre treatment processes, e.g. using pulleys and spindles.

In embodiments, the antimicrobial is dissolved in the treatment solutione.g. entirely dissolved. Advantageously, this allows a homogeneousdistribution of the antimicrobial to be provided within the treatmentsolution, and thereby allows uniform application of antimicrobial to thesubmerged CMC fibres.

It has been surprisingly found that submerging the CMC fibres with atreatment solution containing the anti-microbial in a solvent having thehigh organic content as claimed is able to incorporate theanti-microbial into the fibres at adequate levels to provide suitableelution and antimicrobial properties, but with improved softness andflexibility relative to prior art methods which use aqueous treatmentsolutions. This is exemplified in the examples herein by comparison to acomparative product produced by method whereby an aqueous solution ofPHMB is sprayed onto a CMC wound dressing.

In some embodiments, the antimicrobial is selected from the groupconsisting of a biguanide, octenidine, taurolidine, and a combination oftwo or more thereof. In some embodiments, the antimicrobial is abiguanide. Exemplary biguanides for use in the invention includepolyaminopropyl biguanide (PAPB), polyhexamethylene biguanide (PHMB),metmorfin (dimethylbiguanide), phenformin (phenethylbiguanide),propylbiguanide, buformin (butylbiguanide), hexylbiguanide, alexidineand chlorhexidine, with PHMB being particularly preferred. In someembodiments, the antimicrobial is PHMB, wherein the PHMB polymerbackbone has between 2 and 30 repeating units. Advantageously, PHMB hasbeen shown to have efficacy against a wide range of gram-positive andgram-negative microbes, and therefore is an excellent antimicrobialwithin the field of wound dressings, not least because open wounds mayharbour a plethora of microbial species. PHMB has, for example, beenshown to be effective against Pseudomonas aeruginosa, Staphylococcusaureus (also the methicillin-resistant type, MRSA), Escherichia coli,Candida albicans (yeast), Aspergillus brasiliensis (mold),vancomycin-resistant enterococci, and Klebsiella pneumoniae (implicatedin pneumonia and bronchitis).

In embodiments, the treatment solution may comprise from 1-10 wt % ofthe antimicrobial, optionally 2-8 wt %, or 3-6 wt % antimicrobial, andfurther optionally 4-5 wt %. It has been found that the aforementionedconcentrations of antimicrobial within the treatment solution providesuitable concentrations of antimicrobial in the CMC fibres containingthe antimicrobial.

It may be appreciated that for some anti-microbial compounds, a degreeof water may be required in the treatment solution to assist withsolubility of the anti-microbial in the treatment solution. Thetreatment solution may comprise water in an amount of from 5-25 wt %,optionally 12-20 wt %, further optionally 15-18 wt %. Advantageously, ithas been found that providing a high wt % of organic solvent, optionallyin combination with a moderate (5-25 wt %) amount of water, has beenfound to effectively deliver the antimicrobial into the polymer matrix,and moreover, to prevent gelling of the CMC fibres. For example, inembodiments where the antimicrobial is PHMB, PHMB is highly watersoluble but poorly soluble in organic solvents. It has been found thatproviding a treatment solution of PHMB in a treatment solutioncomprising water and a water-miscible organic solvent effectivelydelivers PHMB into the polymer network, yet advantageously does notresult in gelling of the CMC fibres, unlike with methods wherein aqueoussolutions are used to treat the CMC fibres, such as by spraying.

In some embodiments, the treatment solution comprises the water-miscibleorganic solvent in an amount of from 70-85 wt %, optionally 75-80 wt %,further optionally 76-78 wt %.

The water-miscible organic solvent may be selected from C₁-C₄ alkanols,such as 01-2 alkanols (e.g. ethanol). It may alternatively be a C₃-C₅ketone (e.g. acetone). Combinations of two or more thereof are alsocontemplated. In some embodiments, the water-miscible organic solvent isselected from one or more of methanol, ethanol, propanol, isopropanol,and acetone. In preferred embodiments, the water-miscible organicsolvent comprises, or consists of ethanol. For instance, in someembodiments the water-miscible organic solvent comprises greater than 90wt % ethanol, optionally greater than 95 wt % ethanol, optionallygreater than 97 wt % ethanol. Advantageously, it has been found thatethanol provides CMC fibres containing the antimicrobial that haveparticularly enhanced and desirable softness and flexibility properties,as compared to other water-miscible solvents in accordance with thepresent invention.

In some embodiments, the water-miscible organic solvent is acetone. Insome embodiments, the water-miscible organic solvent is ethanol andacetone, optionally wherein the ratio of ethanol to acetone is from 1:1and 20:1. In some embodiments, the water-miscible organic solvent isethanol and isopropanol, optionally wherein the ratio of ethanol toisopropanol is from 1:1 and 20:1.

In some embodiments, the antimicrobial-containing treatment solution mayfurther comprise a pH adjustment agent, optionally an acid. Inembodiments, the pH adjustment agent provides a pH of from 4.5 to 8.0 inthe treatment solution after the CMC fibres have been submerged in thetreatment solution. In some embodiments, the treatment solutioncomprises 0.1-0.9 wt % hydrochloric acid, optionally 0.4-0.6 wt %hydrochloric acid. Advantageously, the treatment solution comprisingacid may ensure the final pH of the treatment solution, and thereforethe pH of the CMC fibres produced following the treatment step is from4.5 to 8.0.

In embodiments, the treatment solution may further comprise a metal-ioncomplexing agent, such as ethylenediaminetetraacetic acid (EDTA),tetraxetan (DOTA), diethylenetriaminepentaacetic acid (DTPA), and thelike. In some embodiments, the metal-ion complexing agent is EDTA. Thetreatment solution may comprise from 0.1-0.8 wt % metal-ion complexingagent, optionally 0.2-0.7 wt %, optionally still 0.3-0.6 wt %, furtheroptionally 0.4-0.5 wt %. Advantageously, it has been surprisingly foundthat adding a metal-ion complexing agent, such as EDTA, to the treatmentsolution increases the availability of the antimicrobial to penetrateinto the fibre polymer matrix. Metal-ion complexing agents, such asEDTA, are known to exhibit anti-biofilm properties and therefore aredesirable agents for addition to CMC fibres for wound dressings.

In particularly advantageous embodiments, the anti-microbial treatmentprocess as claimed can be performed as an additional step following theinitial preparation of CMC fibres by carboxymethylation of a cellulosestarting material. In embodiments, the CMC fibres submerged in thetreatment solution according to the methods of the invention maytherefore be formed by a process comprising reacting cellulose fibreswith a carboxymethylating agent to provide the CMC fibres. In preferredembodiments, the cellulose fibres are provided as continuous-filamentcellulose. The cellulose fibres may be natural or synthetic. Thecellulose fibres may be derived from wood pulp (e.g. Eucalyptus, Oak,Birch wood). It is known for instance to use such wood pulp materials ina process where they are chemically broken down, and reformed intofibres. Suitable cellulose fibres for use as starting material forforming carboxymethylcellulose include rayon, e.g. viscose, e.g. Lyocellfibres. Optionally, the CMC fibres so formed may be subject to one ormore washes to provide the CMC fibres containing at least 95 wt % CMC bydry mass weight to be submerged in the anti-microbial treatment solutionof the present invention, e.g. to remove undesirable reaction productsor surplus reagents.

Advantageously, it has been found that by preparing CMC fibres in situfrom cellulose fibres, and then treating the resulting CMC fibres withthe treatment solution comprising the antimicrobial according to thepresent claims, CMC fibres of the invention having excellent softnessand flexibility are provided whilst also providing an efficientmanufacturing process. Advantageously, the treatment solution of thepresent method can provide a dual function by virtue of it being able toact as part of the work-up of CMC fibres following carboxymethylation ofcellulose, and by providing an antimicrobial finish to the CMC fibres.

In some embodiments reacting the cellulose fibres with acarboxymethylating agent comprises contacting the cellulose fibres witha base and a carboxymethylating agent, and optionally wherein thecarboxymethylating agent is a chloroacetic acid salt, e.g. amonochloroacetate, preferably sodium monochloroacetate. In typicalembodiments, the base is sodium hydroxide.

The cellulose fibres may be contacted with the base and thecarboxymethylating agent concurrently, or sequentially. In someembodiments, the carboxymethylating agent and base are provided in acarboxymethylating solution and the cellulose fibres are submerged inthe carboxymethylating solution. The carboxymethylating solutioncomprises the carboxymethylating agent, and optionally the base. In someembodiments, the carboxymethylating solution comprises 2-8 wt %carboxymethylating agent (e.g. sodium monochloroacetate), optionally 3-7wt %, optionally still 4-6 wt %, e.g. 5 wt %. In some embodiments, thecarboxymethylating solution comprises 0.5-8 wt % base (e.g. sodiumhydroxide), optionally 1-7 wt %, optionally still 2-4 wt %, e.g. 2.5 wt%. In some embodiments, the carboxymethylating solution furthercomprises greater than 70 wt % of a water-miscible organic solventselected from C₁-C₄ alkanols, C₃-05 ketones, and a combination of two ormore thereof. In some embodiments, the carboxymethylating solutioncomprises the water-miscible organic solvent in an amount of from 70-85wt %, optionally 75-80 wt %, further optionally 76-78 wt %.Advantageously, it has been found that using a solvent of around 70-85wt % water-miscible organic solvent prevents undesirable gelling of theCMC fibres during the manufacturing process. The water-miscible organicsolvent may be selected from any of those listed herein in respect ofthe treatment solution. The water-miscible organic solvent may thus beselected from one or more of methanol, ethanol, propanol, isopropanol,and acetone. In some embodiments, the water-miscible organic solvent isethanol. In some embodiments, the water-miscible organic solventcomprises greater than 90 wt % ethanol, optionally greater than 95 wt %ethanol, optionally greater than 97 wt % ethanol. In some embodimentsthe carboxymethylating solution further comprises water in an amount offrom 5-20 wt %, optionally 7-18 wt %, optionally still 9-16 wt %,further optionally 11-14 wt % e.g. 12 wt %.

In embodiments, the step of reacting the cellulose fibres with acarboxymethylating agent comprises submerging the cellulose fibres in acarboxymethylating solution as described herein, for a duration of from0.5 to 3.5 hours, optionally from 1 to 3 hours, optionally still from1.5 to 2.5 hours, e.g. 2 hours. In some embodiments, thecarboxymethylating solution is maintained at a temperature in a range offrom 55 to 85° C., optionally 60 to 80° C., optionally still 65 to 75°C., and further optionally 68 to 73° C. In some embodiments, followingthe step of submerging the cellulose fibres in the carboxymethylatingsolution, the CMC fibres are allowed to cool to a temperature in therange of from 40 to 60° C., optionally from 45 to 55° C. over a timeperiod of from 10-20 minutes, optionally from 14-16 minutes e.g. 15minutes.

The step of submerging the CMC fibres in the treatment solution may bepreceded by a step of washing the CMC fibres with a pre-treatment washsolution. For instance, in particularly preferred embodiments, the CMCfibres are produced via the CMC-fibre forming step described above andare subjected to a pre-treatment wash solution prior to subjecting theCMC-fibres to the anti-microbial treatment step. This has the advantageof allowing certain by-products of the forming step, or otherundesirable compounds to be removed prior to the anti-microbialtreatment step. Preferably, the pre-treatment wash solution comprises:

-   -   (i) greater than 70 wt % of a water-miscible organic solvent        selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a combination        of two or more thereof; and optionally    -   (ii) a pH adjustment agent, optionally an acid.

A particularly preferred method is therefore a method of manufacturingcarboxymethylcellulose (CMC) fibres containing an antimicrobial, thefibres being suitable for use in the preparation of wound dressings,wherein the antimicrobial is selected from the group consisting of abiguanide, a biguanide derivative, octenidine, taurolidine, and acombination of two or more thereof, the method comprising:

-   -   a) forming CMC fibres by a process comprising reacting cellulose        fibres with a carboxymethylating agent to provide the CMC        fibres; and    -   b) washing the formed CMC fibres with a pre-treatment wash        solution, the pre-treatment wash solution comprising greater        than 70 wt % of a water-miscible organic solvent selected from        C₁-C₄ alkanols, C₃-C₅ ketones, and a combination of two or more        thereof; and optionally a pH adjustment agent, such as an acid,        to provide pre-treated CMC fibres comprising at least 97 wt %        carboxymethylcellulose on a dry weight basis; and    -   c) submerging the pre-treated CMC fibres in a treatment        solution, the treatment solution comprising:        -   a. the antimicrobial; and        -   b. at least 70 wt % of a water-miscible organic solvent            selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a            combination of two or more thereof;    -   for a duration adequate to provide the CMC fibres containing an        antimicrobial.

In some embodiments, the pre-treatment wash solution comprises a pHadjustment agent (e.g. acid), optionally wherein the pH adjustment agentprovides a pH of from 4.5 to 8.0, when the CMC fibres are submerged inthe pre-treatment wash solution. The pH adjustment agent may be a base,an acid, or a buffer. In some embodiments, the pH adjustment agent is anacid, e.g. HCl.

The optional pH adjustment agent allows the pH of the CMC fibres to beadjusted to a suitable range prior to exposure of the pre-treated CMCfibres to the anti-microbial agent during the treatment step. Usuallythe anti-microbial is a relatively expensive component and so it ispreferred to ensure that the pH is suitable for the givenanti-microbial. In the case of biguanides such as PHMB, it isadvantageous to ensure a pH in the pre-treatment solution of 4.5 to 8.

In some embodiments, the pH adjustment agent is an acid, e.g. HCl. Thisis for instance a suitable pH adjustment agent in the case whereby theCMC fibres are formed via a method comprising reactingcarboxymethylating agent with cellulose in the presence of base (wherebythe acid may neutralise an excess base and ensure any residual salts aredissolved).

Washing the CMC fibres with the pre-treatment wash solution may beperformed by any suitable wash method, and may typically includesubmerging the CMC fibres in the pre-treatment wash solution, e.g. in abath containing the pre-treatment wash solution. In some embodiments,the CMC fibres are submerged in the pre-treatment wash solution. In someembodiments, the CMC fibres are washed with, optionally submerged in,the pre-treatment wash solution of a duration of from 15 to 35 minutes,optionally 20 to 30 minutes, optionally still from 22 to 27 minutes,e.g. 25 minutes.

Advantageously, the pre-treatment wash solution causes the polymermatrix within the CMC fibres to expand/swell, and may remove anyundesirable contaminants on the CMC fibres. Without wishing to be boundby theory, it is thought that causing the polymer matrix to expand/swellimproves the penetration of the antimicrobial in the treatment solutionthroughout the polymer matrix.

CMC fibres may comprise basic salts, which require neutralisation byacid. These basic salts may be residually present from the manufacturingprocess of CMC, which typically requires the use of strong bases such assodium hydroxide. In embodiments of the first aspect of the presentinvention described above wherein CMC fibres are prepared in situ fromcellulose fibres, the pre-treatment wash solution comprises acid, e.g.HCl to neutralise residual base from the carboxymethylation step.

In some embodiments the pre-treatment wash solution compriseshydrochloric acid, optionally 0.1-0.9 wt % hydrochloric acid, furtheroptionally 0.4-0.6 wt % hydrochloric acid. Advantageously, theneutralisation products of hydrochloric acid with the base typicallyused in carboxymethylation of cellulose (sodium hydroxide) are sodiumchloride and water, both of which do not adversely affect the patientnor the performance of wound dressings comprising the CMC fibres.Moreover, advantageously, because of the high content (greater than 70wt %) of water-miscible organic solvent in the pre-treatment washsolution, neutralisation salts such as sodium chloride may precipitateout of the pre-treatment wash solution, and are therefore removed fromthe CMC fibres.

In embodiments, the pre-treatment wash solution may comprise water in anamount of from 5-25 wt %, optionally 12-20 wt %, further optionally15-18 wt %. Advantageously, as described above in respect of thetreatment solution, it has been found that providing a high wt % oforganic solvent in combination with a moderate (5-25 wt %) amount ofwater has been found to prevent gelling of the CMC fibres whilstallowing removal of impurities.

In embodiments, the pre-treatment wash solution comprises thewater-miscible organic solvent in an amount of from 70-85 wt %,optionally 75-80 wt %, further optionally 76-78 wt %. Advantageously, ithas been found that around 70-85 wt % water-miscible organic solventprevents undesirable gelling of the CMC fibres during the manufacturingprocess.

In some embodiments the treatment solution and/or the pre-treatment washsolution is maintained at a temperature within the range of from 20° C.to 50° C. during the submerging step.

In embodiments, the CMC fibres may be submerged in the treatmentsolution for a duration of from 15 to 35 minutes, optionally from 20 to30 minutes, and optionally still from 22 to 27 minutes, e.g. 25 minutes.

The step of submerging the CMC fibres in treatment solution according tomethods of the invention may be followed by washing the CMC fibrescontaining antimicrobial with a post-treatment wash solution, thepost-treatment wash solution preferably comprising:

-   -   (i) at least 98 wt % of a water-miscible organic solvent        selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a combination        of two or more thereof; and optionally    -   (ii) a spin finish agent (which may be a surfactant), optionally        from 0.1-2.0 wt % or 1-1.5 wt % spin finish agent (e.g.        surfactant).

In some embodiments the post-treatment wash solution comprises water inan amount of from 0.01-1.9 wt %, optionally 0.1-1.5 wt %, furtheroptionally 0.5-1 wt %. In some embodiments the pre-treatment washsolution comprises the water-miscible organic solvent in an amount of atleast 99 wt %.

Advantageously, submerging the CMC fibres in a post-treatment washsolution comprising predominately (at least 98 wt %) water-miscibleorganic solvent draws water out of the polymer matrix in the CMC fibres,which assists in the drying of the CMC fibres as described below.Moreover, advantageously, particularly where the antimicrobial iswater-soluble (e.g. PHMB) but not soluble in organic solvents (e.g.PHMB), the post-treatment wash solution being predominatelywater-miscible organic solvent avoids washing the antimicrobial out ofthe CMC fibres.

In preferred embodiments, the post-treatment wash solution mayadvantageously comprise a spin finish agent and or surfactant. The spinfinish agent may be a surfactant. Examples include polysorbates, e.g.Polysorbate 20 (Tween).

In embodiments, the method may further comprise removing solvent fromthe CMC fibres containing the antimicrobial, wherein the removingincludes performing one or more of air drying, mechanical pressing,centrifugation, oven drying and vacuum extraction. The solvent to beremoved may be the water-miscible organic solvent from the treatmentsolution and/or the post-treatment wash solution, and/or water. Inembodiments, the removing may include oven drying at a temperature offrom 25 to 40° C. for a duration of from 10 to 20 hours, optionally 14to 18 hours. This has the effect that solvent is removed from the CMCfibres such that only residual amounts of water and/or water-miscibleorganic solvent remain in the fibres. Advantageously, removal of waterfrom the CMC fibres prevents any undesired gelling of the fibresoccurring during periods of storage of the CMC fibres and/or wounddressings comprising the CMC fibres.

In a preferred embodiment of the first aspect of the present inventionis provided a method of manufacturing carboxymethylcellulose (CMC)fibres containing polyhexamethylene biguanide (PHMB), the fibres beingsuitable for use in the preparation of wound dressings, the methodcomprising:

-   -   (i) forming CMC fibres by a process comprising reacting        cellulose fibres with a carboxymethylating agent to provide        carboxymethylcellulose (CMC) fibres comprising at least 95 wt %        CMC by dry weight basis (e.g. at least 97 wt %); and    -   (ii) submerging the CMC fibres in a pre-treatment wash solution        comprising        -   a. greater than 70 wt % of a water-miscible organic solvent            selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a            combination of two or more thereof; and optionally        -   b. and pH adjustment agent adequate to maintain a pH in the            treatment solution of pH 4-8; and    -   (iii) submerging the pre-treated CMC fibres in a treatment        solution comprising:        -   a. from 1-10 wt % PHMB; and        -   b. at least 70 wt % of a water-miscible organic solvent            selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a            combination of two or more thereof; for a duration adequate            to provide CMC fibres containing PHMB; and    -   (iv) submerging the CMC fibres containing PHMB in a        post-treatment wash solution comprising:        -   a. at least 98 wt % of a water-miscible organic solvent            selected from C₁-C₄ alkanols, C₃-C₅ ketones, and a            combination of two or more thereof; and        -   b. a spin finish agent (which may be a surfactant),            optionally from 0.1-2.0 wt % spin finish agent (which may be            a surfactant); and    -   (v) optionally removing solvent from the CMC fibres containing        the antimicrobial.

In some embodiments of the above process, all of the optional featuresare present. In some embodiments, the CMC fibres comprise from 0.05 to0.8 carboxymethyl groups per glucose unit, optionally from 0.5 to 0.75carboxymethyl groups per glucose unit, as determined by potentiometrictitration.

In some embodiments, the carboxymethylcellulose (CMC) fibres containingthe antimicrobial contain the antimicrobial dispersed throughout thefibre. Advantageously, the method of submerging the CMC fibres in thetreatment solution comprising the antimicrobial causes the polymermatrix to expand, and the antimicrobial is able to penetrate into theCMC fibres. Moreover, by submerging the CMC fibres in the treatmentsolution, a larger surface area of the CMC fibre is exposed to theantimicrobial, and as such, it is anticipated that a more evendistribution of antimicrobial is provided throughout the CMC fibre ascompared to prior art methods such as spraying antimicrobial solutionsonto fibres.

In embodiments, the method further comprises forming a wound dressing,or an article suitable for use in a wound dressing, comprising therespective (CMC) fibres containing the antimicrobial. The presentdisclosure thus contemplates use of the (CMC) fibres containing theantimicrobial obtained by the methods herein (e.g. fibres as describedaccording to any of aspects two to four) in a method of forming a wounddressing, or forming an article suitable for use in a wound dressing.The fibres may be used to form a woven or non-woven article/material,preferably non-woven. For instance, forming the article/material maycomprise weaving the fibres. Forming the article/material may comprisesubjecting the fibres to needling/carding, e.g. to form a felt. Thematerials/wound dressing may be as described in accordance with any ofthe fourth to seventh aspects and embodiments herein.

According to a second aspect of the present invention, there is provideda carboxymethylcellulose (CMC) fibre containing an antimicrobial for usein the preparation of wound dressings, the CMC fibre obtained orobtainable by a method according to the first aspect of the presentinvention or any embodiments thereof. The definition of theantimicrobial presented in the first aspect and embodiments maytherefore apply to this aspect.

According to a third aspect of the present invention, there is provideda carboxymethylcellulose (CMC) fibre containing an antimicrobialselected from a biguanide, a biguanide derivative, octenidine,taurolidine, and a combination of two or more thereof for use in thepreparation of wound dressings wherein the antimicrobial is dispersedthroughout the fibre polymer. In desirable embodiments, theanti-microbial is present throughout the body of the fibre and notsimply at the surface. It is believed that this can be afforded bymethods of the invention by virtue of the fibre polymer swelling in thetreatment solution to allow ingress of the anti-microbial.

A fourth aspect provides a carboxymethylcellulose (CMC) fibre containingan antimicrobial selected from a biguanide, a biguanide derivative,octenidine, taurolidine, and a combination of two or more thereof foruse in the preparation of wound dressings, wherein the CMC fibre polymerhas not undergone gelation.

It is intended that the CMC fibres comprising antimicrobial according tothe present invention may comprise additional additives, such asadditives known to be useful in wound dressing applications. Suchadditives may include surfactants, spin finish agents and/oranti-biofilm agents (such as chelating agents, e.g. EDTA/DTPA). The spinfinish agent may be a surfactant. Suitable spin finish agents includepolysorbate, e.g. polysorbate 20 (Tween). In embodiments, such additivesare provided in a total amount of no more than 5 wt %, e.g. no more than4 wt %, 3 wt %, 2 wt % or 1 wt %. The CMC fibres of the invention may beabsent of such additives.

The CMC fibres comprising antimicrobial according to the presentinvention (e.g. as defined in the second to fourth aspects herein) maycomprise at least 95 wt % CMC relative to the total dry mass weight ofthe fibre, optionally at least 96 wt %, 97 wt %, 98 wt %, or optionallyat least 99 wt %. Preferably, the CMC fibres are entirely absent of anyother fibre polymers. Preferably the CMC fibres are absent of alginates.

According to a fifth aspect of the present invention, there is provideda woven, non-woven or knitted material comprising CMC fibres containingan antimicrobial, wherein the CMC fibres containing an antimicrobial aredefined according to any one of the second, third or fourth aspects ofthe invention. The material is preferably a non-woven and mostpreferably a felt. The non-woven material may exhibit a conformabilitycharacterised by an overhang length of up to 6.5 cm, as determined bythe Cantilever method described in ASTM D1388-08. Standardised methodsfor preparing the non-woven for testing by the Cantilever method aredescribed herein in the general methods section (see conformabilitytesting). The overhang length in the longitudinal direction maytypically be from 4 to 6.5 cm, e.g. 4 to 6 cm. The overhang length inthe longitudinal direction may in embodiments be no more than 6.2 cm,e.g. no more than 6 cm. In embodiments, this value is no more than 5.8cm, 5.5 cm, or 5.3 cm. Preferably, the value is no more than 5.5 cm,e.g. no more than 5.0 cm.

According to a sixth aspect of the present invention, there is provideda non-woven material (preferably a felt) comprising entangled CMC fibrescontaining an antimicrobial, wherein the antimicrobial is selected froma biguanide, a biguanide derivative, octenidine, taurolidine, and acombination of two or more thereof, wherein the non-woven materialexhibits a conformability characterised by an overhang length of up to6.5 cm, as determined by the Cantilever method described in ASTMD1388-08. Standardised methods for preparing the non-woven for testingby the Cantilever method are described herein in the general methodssection (see conformability testing). The overhang length in thelongitudinal direction may typically be from 4 to 6.5 cm, e.g. 4 to 6cm. The overhang length in the longitudinal direction may in embodimentsbe no more than 6.2 cm, e.g. no more than 6 cm. In embodiments, thisvalue is no more than 5.8 cm, 5.5 cm, or 5.3 cm. Preferably the overhanglength in the longitudinal direction is no more than 5.5 cm, e.g. nomore than 5.0 cm. Methods described herein advantageously allowproduction of CMC fibres containing an anti-microbial agent whilstavoiding premature gelation. This therefore ensures that the CMC fibresretain softness, enabling production of resulting wound dressings thatcontain anti-microbial agent, but which still exhibit desirableconformability, as demonstrated by the relatively low overhang lengthsrecited, as determined by the Cantilever method.

According to a seventh aspect of the invention, there is provided awound dressing comprising CMC fibres containing an antimicrobial,wherein the CMC fibres containing an antimicrobial are defined accordingto any one of the second, third or fourth aspects of the invention. Thewound dressing may for instance contain a material according to thefifth or sixth aspects of the invention and the material is preferably afelt. The wound dressing may contain the material as the sole layer ofthe wound dressing, or typically the wound dressing may be a multi-layerdressing wherein the material is present as a layer within themulti-layer dressing.

In the CMC fibres containing anti-microbials of the invention, or thematerials or wound dressings comprising such materials as defined in anyof the second to seventh aspects herein, the antimicrobial may bepresent in the fibre in an amount of from 0.3 to 1.1 wt %, optionallyfrom 0.5 to 0.9 wt %. In the CMC fibres containing anti-microbials, orthe materials or wound dressings comprising such materials as defined inany of the second to seventh aspects herein, the antimicrobial may beselected from the group consisting of a biguanide, octenidine,taurolidine, and a combination of two or more thereof. In someembodiments, the antimicrobial is a biguanide. Exemplary biguanides foruse in the invention include polyaminopropyl biguanide (PAPB),polyhexamethylene biguanide (PHMB), metmorfin (dimethylbiguanide),phenformin (phenethylbiguanide), propylbiguanide, buformin(butylbiguanide), hexylbiguanide, alexidine and chlorhexidine, with PHMBbeing particularly preferred. In some embodiments, the antimicrobial isPHMB, wherein the PHMB polymer backbone has between 2 and 30 repeatingunits. In any embodiments, the antimicrobial may be dispersed throughoutthe CMC fibre. In any embodiments, the carboxymethylcellulose (CMC)fibre containing an antimicrobial has desirably not undergone gelation.

Wound dressings in accordance with the seventh aspect of the presentinvention may be a multi-layer wound dressing comprising a non-wovenfabric layer prepared using CMC fibres containing an antimicrobialaccording to the present invention, and one or more additional layers.The non-woven fabric layer may comprise greater than 98 wt % CMC fibrescontaining an antimicrobial according to the present invention,optionally greater than 99 wt %. The non-woven fabric layer may be awound-contacting surface, or may be embedded between other layers in themulti-layer wound dressing. The multi-layer wound dressing may comprisea perforated wound-contacting layer, for example a perforatedwound-contacting layer comprising polyurethane, which allows passage ofexudate from the wound to the non-woven fabric layer. In someembodiments, the perforated wound-contacting layer further comprises anadhesive to adhere to the patient's skin. In some embodiments, themulti-layer wound dressings further comprise a semi-permeable layer, afilm backing layer (e.g. polyurethane), a hydrocolloid and/or afoam-based layer. Advantageously, semi-permeable layers may assist ingenerating a moist environment for wounds to heal. In some embodiments,the non-woven fabric layer is between a perforated wound-contactinglayer and a semi-permeable layer. Advantageously, this arrangement mayincrease absorbance of exudate from the wound, and/or improve fluidretention properties within the wound dressing.

A preferred wound dressing of the invention may comprise reinforcednon-woven felt comprising a non-woven layer containing between 120-185gsm of CMC fibres containing PHMB, the CMC fibres containing PHMB beingneedle bonded to a reinforcement layer of nominally 15-55 gsm made ofnylon 6.6. Alternatively, reinforcing layers materials other than nylon6.6 may be used, such as cellulose, polypropylene, polyester, PET, etc.

In some embodiments, the wound dressings may be a single layer wounddressing comprising a non-woven fabric layer prepared using CMC fibrescontaining an antimicrobial according to the present invention. Thenon-woven fabric layer may comprise greater than 95 wt %, e.g. at least96 wt %, 97 wt %, 98 wt % or at least 99 wt % CMC fibres containing anantimicrobial according to the present invention, optionally greaterthan 99 wt %. In such embodiments, the wound dressing may be used inconjunction with a secondary wound dressing, wherein the secondary wounddressing includes a semi-permeable layer.

This disclosure also provides use of a) the fibres according to any ofthe second to fourth aspects and embodiments thereof described herein,or b) the material according to the fifth or sixth aspects orembodiments thereof described herein, or c) the wound dressing accordingto the seventh aspect or embodiments thereof described herein, in woundcare, e.g. wound healing, or in a method of treating a wound. Thisapplication also provides a method of wound care, e.g. wound healing, ortreating a wound, comprising applying the wound dressing according tothe seventh aspect of the invention or any embodiment thereof to thewound. Also provided are CMC fibres containing an antimicrobialaccording to the second, third or fourth aspect or any embodimentthereof, for use in a method of treating a wound, or in wound care, e.g.wound healing, wherein the fibres are provided in a wound dressingaccording to the seventh aspect or any embodiment thereof, and themethod comprises applying the wound dressing to the wound. Also providedis the use of CMC fibres containing an antimicrobial according to thesecond, third or fourth aspect or any embodiment thereof, in themanufacture of a wound dressing for treating a wound, or for wound care,e.g. for wound healing, wherein the treating comprises applying thewound dressing to the wound. The antimicrobial may be as describedaccording to any embodiment herein, and is preferably PHMB. Theantimicrobial may be as described according to any embodiment herein,and is preferably PHMB.

EXAMPLES

The following examples provide test methods and describe embodiments ofthe methods and products of the invention. The examples are intended toexemplify the invention but are not intended to be limiting on the scopeof protection.

General Methods

Cantilever Test—Conformability Assay

The conformability of a non-woven fabric consisting of CMC fibrescontaining PHMB that were prepared according to the method of thepresent invention were investigated and comparative to theconformability of a comparative dressing not prepared according to theinvention. This is described in example 5.

Several methods are known in the art for assessing the conformabilityand stiffness of fabrics, such as the cantilever test and the heart looptest. The data disclosed herein was obtained using the cantilever testas outlined below, and was in accordance with the cantilever method asapproved by the American Society for Testing and Materials (ASTM)International (Designation D1388-08). The cantilever test employs theprinciple of cantilever bending of the fabric under its own weight.

A cantilever bending test apparatus (“Shirley Stiffness tester”) havinga horizontal surface was used for the conformability assay. Suchapparatus are commercially available and described in detail in section6 entitled “apparatus” in ASTM D1388-08, which is incorporated herein byreference. In accordance with the conformability Cantilever testdescribed herein, the non-woven fabric for testing was prepared by thefollowing method.

The CMC fibres to be tested (which may include anti-microbial inaccordance with the invention) are opened and carded to form a non-wovenstructure comprising a nominal fibre weight between 125-185 GSM andneedle-bonding density of 60-120 punches per square centimetre. Theresulting non-woven felt is slit and cut to the required size to form anon-woven dressing ready for subjecting to the Cantilever methoddescribed below.

Samples of non-woven fibrous dressing as prepared by the method aboveand cut to a size of 25 mm×150 mm were slid along the horizontal surfaceat a rate of around 120 mm/min (+/−5%) in a direction parallel to anotional ‘long dimension’ of the sample. The sample was slid along thehorizontal surface so that a leading edge projected from an edge of thehorizontal surface. Sliding of the sample continued until the leadingedge of the sample was depressed under the influence of gravity to thepoint where the angle formed between the leading edge and the horizontalsurface was 41.5°. In other words, the weight of the overhang length ofthe sample causes the overhang length to depress under its own weight toan angle of 41.5° relative to the horizontal surface. The length of theresulting overhang was measured (in cm). From the measured lengths, thebending length was calculated, as described below under Example 5.

Owing to the non-directional orientation of fibres within non-wovenfabrics, the method was repeated for each sample wherein the sample wasrotated by 90° C. about its central axis perpendicular to the horizontalsurface. In other words, the sample was rotated such that the sample wasslid along the horizontal surface in a direction parallel to a notional‘short’ dimension of the sample.

Example 1—Preparation of CMC Fibres Containing PHMB from CelluloseFibres

A cellulose continuous filament (1.25 kg) of cellulose fibres wassubmerged in a carboxymethylating solution comprising 2.5 wt % sodiumhydroxide, 13.5 wt % purified water (1.66 kg), 5 wt % sodiumchloroacetate and 78 wt % ethanol. The resulting suspension wasmaintained at a temperature in the range of from 65 to 75° C., typicallyabout 70° C., for a duration of around 2 hours.

The carboxymethylated cellulose continuous filament andcarboxymethylating solution was allowed to cool to a temperature in therange of from 45° C. to 55° C., typically to about 50° C. and theresulting carboxymethylated cellulose continuous filament was thenwashed with a pre-treatment wash solution comprising 78 wt % ethanol,21.5 wt % distilled water and 0.5 wt % hydrochloric acid to removeunreacted salts remaining from the carboxymethylation step andneutralise excess base. The wash was performed for around 25 minutes, ata temperature in the range of from 20° C. to 50° C., typically about 45°C. The pH of the wash solution after 20 to 30 minutes was between 4.5and 8.0. The washed carboxymethylated cellulose continuous filament wasthen removed from the wash solution and subject to a treatment solutioncontain anti-microbial (PHMB). Other anti-microbials described hereinmay alternatively be provided.

The carboxymethylated cellulose continuous filament was submerged in aPHMB treatment solution comprising 4 wt % PHMB, 77 wt % ethanol, 0.4 wt% EDTA, 0.5 wt % hydrochloric acid, and 17 wt % purified water for 20 to30 minutes at a temperature in the range of from 20° C. to 50° C.,typically about 45° C., thus providing carboxymethylated cellulosecontinuous filament comprising PHMB. The carboxymethylated cellulosecontinuous filament comprising PHMB was then removed from the PHMBtreatment solution. Other components suitable for wound dressingapplications may also optionally be included in the treatment solution,such as anti-biofilm agents, or surfactants.

The carboxymethylated cellulose continuous filament comprising PHMB wasthen submerged in a final post-treatment wash solution comprising 99 wt% ethanol and 1 wt % polysorbate 20 (Tween) to remove excess water orother surplus materials, and provide desirable soft feel of the fibres,at a temperature in the range of from 20° C. to 50° C., typically around45° C., for a duration of from 20 to 30 minutes. This post-treatmentwash step may optionally be repeated if desired.

The carboxymethylated cellulose continuous filament comprising PHMB wasthen removed from the final wash solution, and dried by means of vacuumat a temperature of 40° C. to provide the dried carboxymethylatedcellulose continuous filament comprising PHMB. The fibres weredetermined to contain 0.6% wt PHMB relative to the total weight of thefibres.

Example 2—Preparation of Non-Woven Felt Fabric

Those skilled in the art will be familiar with methods for preparingnon-woven fabrics from fibres. An exemplary method is described below.

Continuous filaments of CMC fibres containing PHMB, prepared inaccordance with Example 1, were cut into sections approximately 50 mm(2″) in length. The sections of CMC fibres were separated from clumps offibres into individual fibres using a coarse combing action. This stagemay be referred to as ‘fibre opening’. Following fibre opening, the CMCfibres were subjected to a finer combing action to separate all thefibres into individual fibres and to create a coherent, lightweight web,typically in the 10-20 g/m² range. The fibres in the web were orientatedin the machine direction of the produced web. This stage may be referredto as ‘carding’. Following carding, the web of CMC fibres wascrosslapped with another layer of carded web. This process was continueduntil a density of nominally 150 g/m² was achieved was achieved. Eachweb layer was overlaid at 90° (in the cross direction) to the precedingweb layer. This stage may be referred to as “crosslapping”. Followingcrosslapping, a plurality of barbed needles were punched into thelayered web produced during carding and removed therefrom multipletimes. CMC fibres from the surface web layer were thereby drawn intoother layers of the layered web structure, thereby entangling the fibresto create the felt. Of course, fibres in other web layers were alsodrawn into other layers.

Those skilled in the art will understand that the quantity and type ofneedles, the speed of needling and the penetration depth effect theproperties of the resulting felt fabric. In the present examples, theprocess applied a 9 mm needle penetration depth at a needle board speedof 220 RPM. The needling action can be carried out in more than stage,and may be performed from one or both sides of the fibres.

Example 3—Preparation of Wound Dressing

Anti-microbial materials according to the invention, such as non-wovensas described above, may be incorporated into wound dressings inconventional ways. For instance, the anti-microbial material may beprovided with a suitable backing layer and/or a skin contact layer,which may, in embodiments, be windowed. The backing layer and/or woundcontact layer may be provided with an adhesive to assist the fixing ofthe wound dressing to the wound, such as a low trauma adhesive, e.g. asilicone adhesive.

Example 4—Gelling Test for CMC Fibres Containing PHMB

Approximately 4 cm of continuous filament CMC fibres containing PHMBprepared in accordance with Example 1 were cut. The fibres wereseparated out (‘fibre opening’) and dipped in distilled water for aminimum of 10 seconds. The fibres were withdrawn from the water andgelling visually inspected, wherein gelling was observed and gelledfibres were observed to be transparent.

Example 5—Conformability and Flexibility Testing

A non-woven fabric (Sample A) comprising CMC fibres containing PHMBaccording to the present invention was prepared according to the methoddescribed in Example 2. A comparative non-woven fabric comprising CMCfibres without PHMB incorporated, prepared by subjecting conventionalCMC fibres to the method of example 2, was then prepared and sprayedwith an aqueous solution of PHMB (Sample B). Spraying was performed asfollows: an aqueous 20% PHMB solution was sprayed such that 1 gram ofstock solution was sprayed onto the non-woven and the resultingconcentration, which was calculated to amount to 0.6% of PHMB on thefinished dressing, for comparison with Sample A of the invention. Thesprayed samples were left to dry for a minimum of 16 hours.

Once prepared, Sample A was cut into six samples of 25×150 mm fortesting in accordance with the cantilever method outlined above.Similarly, Sample B was cut into six comparative sized samples fortesting. Each sample was slid in two directions with respect to thefabric: along the ‘long’ dimension, and along the ‘short’ dimension, asexplained above. The results for each sample are set out in the tablebelow.

For each sample, the test was conducted with the sample initiallynotionally ‘facing upwards’ (i.e. surface not in contact with thehorizontal surface) with a notional ‘front edge’ leading towards theedge of the horizontal surface. The test was repeated with the samplefacing upwards with the other ‘back edge’ leading. The test was repeatedwith the sample facing downwards (‘reverse face’) with the front edgeleading. Finally, the test was repeated with the sample facing downwardswith the back edge leading.

Face FE: Face upwards, front edge leading; Face BE: Face upwards; backedge leading; Reverse FE: Reverse upwards; front edge leading; ReverseBE: Reverse upwards; back edge leading.

TABLE 1 Long Dimension Sample A (cm) Sample B (cm) Face Face ReverseReverse Face Face Reverse Reverse FE BE FE BE FE BE FE BE 1 4.05 4.004.90 4.75 6.00 6.30 7.40 7.35 2 4.10 4.25 5.20 4.95 5.90 5.95 6.50 6.303 4.15 3.95 4.90 5.00 6.15 6.60 7.45 7.25 4 4.25 4.30 4.80 4.90 7.006.95 7.35 7.05 5 4.00 4.15 4.85 5.05 7.00 6.90 7.45 7.55 6 4.25 4.055.10 5.00 6.85 7.00 7.40 7.35 Avg. 4.13 4.12 4.96 4.94 6.48 6.62 7.267.14 Std 0.10 0.14 0.16 0.11 0.52 0.42 0.37 0.44 Dev

TABLE 2 Short Dimension Sample A (cm) Sample B (cm) Face Face ReverseReverse Face Face Reverse Reverse FE BE FE BE FE BE FE BE 1 4.60 4.654.80 4.70 5.45 5.25 5.20 5.20 2 4.40 4.35 4.70 4.65 4.80 4.65 5.00 5.053 4.50 4.40 4.55 4.65 5.35 5.55 5.65 5.50 4 4.55 4.55 4.65 4.60 4.854.65 4.75 4.80 5 4.65 4.60 4.50 4.60 4.85 4.80 4.70 4.60 6 4.35 4.454.60 4.65 4.95 4.90 4.95 4.80 Aver- 4.51 4.50 4.63 4.64 5.04 4.97 5.044.99 age Std 0.12 0.12 0.11 0.04 0.28 0.36 0.35 0.33 Dev

The total averages and standard deviation for the long dimension (Table3) and the short dimension (Table 4) are shown below.

TABLE 3 Long Direction Sample A (cm) Sample B (cm) Total Average 4.546.88 Std Dev 0.026 0.061

TABLE 4 Short Direction Sample A (cm) Sample B (cm) Total Average 4.575.01 Std Dev 0.04 0.03

As can be seen from Tables 3 and 4, Sample A (according to theinvention) demonstrated bending at shorter lengths compared to Sample B(comparative example not according to the invention prepared by sprayingdressing with aqueous PHMB solution), indicative of greaterconformability for the wound dressing containing fibres prepared bymethods of the present invention compared to the comparative example.This difference was most pronounced for tests performed in the notional‘longitudinal’ direction (4.54 cm) on average, as compared to Sample B,which revealed a much longer length for fabric folding (6.88 cm) onaverage. These data are clearly indicative of increased softness andflexibility of the CMC fibres prepared according to the presentinvention and the resulting wound dressings prepared using such fibresaccording to the present invention.

Example 6—Antimicrobial Elution

A non-woven fabric prepared as described for Sample A under Example 5,and a comparative fabric not according to the invention, prepared in themanner described above for Sample B under Example 5, were tested todetermine PHMB elution properties. The sample preparation and testmethod determination was conducted identically for both samples.

For each sample, a cut corresponding to 0.16 grams of the givennon-woven fabric was gravimetrically measured. Each sample was placed in100 g deionised water in a sample container and the sample lightlysqueezed to ensure saturation with the water. The sample container wascovered to prevent evaporation and left at ambient temperature forperiods of 24 h, 48 h and 96 h (+/−30 min). After these respectiveperiods, the PHMB concentration in the sample water, corresponding toeluted PHMB, was determined by photospectroscopic absorption using aJenway 7305 UV-Vis Spectrometer, set to scan at 236 nm. This wasperformed by first running a blank control sample containing 3 mLdeionised water in a 10 mm path-length quartz cuvette, followed byrunning a cuvette containing 3 mL of the given PHMB sample. A readingwas obtained from the spectrometer for the sample, and the sample wasrotated by 180 degrees before the reading was recorded again and themean absorbency for the two readings calculated. This was performed forsamples A and B at each of the above time frames, i.e. 24 h, 48 h and 96h.

If the mean absorbance value is less than 0.592, the actual PHMB levelcan be obtained in ppm by multiplying the sample absorbance by 169. Ifthe absorbance reading is greater than 0.592, the PHMB concentration isgreater than 100 ppm and the solution should be diluted 10-fold until asuitable reading less than 0.592 is obtained, whereby the multiplicationfactor of 169 can be used, and the relevant dilution factored in. PHMBelution demonstrated by samples of the invention (referred to as SampleA) and the comparative samples (Sample B) are shown in table 5, wherebythe values indicate the eluted concentration of PHMB in the solution inppm at the defined time-periods.

TABLE 5 Time Sample A (Invention) Sample B (comparative) period PHMBelution in ppm PHMB elution in ppm 24 Hrs 14.11 13.25 std dev: 0.848 stddev: 1.367 48 Hrs 15.70 15.04 std dev: 2.093 std dev: 2.245 96 Hrs 15.9416.80 std dev: 1.6228 std dev: 3.2047

The data show that sample A of the invention desirably elutes PHMB anddoes so at a rate that is similar to the comparative example (Sample B).

Example 7—Antimicrobial Analysis

The Medicines & Healthcare Products Regulatory Agency (MHRA) and US Foodand Drug Administration (FDA) require antimicrobial products, such aswound dressings prepared using the CMC fibres containing anantimicrobial in accordance with the present invention, to generate a 4log reduction against a range of microorganisms. A 4 log reduction meansthe starting level of microorganisms is reduced by a factor of 10,000(10⁴), for example, typically starting levels in these tests would be1×10⁶ colony forming units (CFU), these need to be reduced to at least1×10² (100) or less. This translates into a 99.99% reduction of theinoculated bacterial population.

Test method AATCC100 “Antimicrobial Finishes on Textile Materials:Assessment of” is deemed as a suitable method to perform antimicrobialanalysis. The AATCC-100 method was performed with the indicatedmicroorganisms below and with samples of non-woven wound dressingsprepared using the CMC fibres containing PHMB in accordance with thepresent invention. The log-fold reduction in bacteria are indicated inTable 6.

TABLE 6 Microorganisms Type AATCC-100 MRSA Gram + >6log MRSEGram + >6log VRE Gram + >6log Strep. Pyogenes Gram + >4log Pseud.Aeruginosa Gram − >6log E. Coli Gram − >6log Kleb. Pneumoniae Gram− >5log C. Albicans Yeast >6log Rh. Mucilaginosa Yeast >6log Trich.Mentagrophytes Mould >4log Asp. Fumigatus Mould >5log

As can be seen in Table 6, samples of wound dressings prepared using CMCfibres containing PHMB in accordance with the present invention wereeffective against a wide range of microorganisms including gram −ve andgram +ve bacteria, yeast, and moulds. Moreover, the log-fold reductionin bacterial growth for each microorganism tested was for all microbestested at least 4, showing desirable efficacy in line with therequirements of the MHRA and FDA as outlined above.

In summary, from the data above, it is evident that the CMC fibrescontaining anti-microbial prepared according to the present inventionprovide desirable elution properties and an excellent anti-microbialeffect in practice. The dressings provide these desirable functionalproperties whilst advantageously providing improved conformabilitycompared to anti-microbial CMC wound dressings prepared according toprior art methods (e.g. whereby CMC dressings are sprayed with anaqueous solution of PHMB), thus providing improved wound dressings whichwould be more comfortable and effective for patients.

The methods of the invention can also be conveniently incorporateddirectly into the CMC-fibre forming process as described in detailabove. This is possible without the need for additional drying ormanipulation of the CMC fibre, but instead by taking the formedCMC-fibre material directly and applying a suitable wash regime, whichmay include submerging the CMC-fibre in an anti-microbial treatmentsolution as described in the first aspect of the invention.

Although the present invention has been described in detail, it shouldbe understood that various changes, substitutions, and alterations arecontemplated without departing from the principle and scope of theinvention. Accordingly, the scope of the present invention should bedetermined by the following claims and their appropriate legalequivalents. The terms “a”, “an” and “the” do not preclude the presenceof multiple referents, unless the context clearly dictates otherwise.Optional or optionally means that the feature or activity may or may notbe present. Either is contemplated. In embodiments, the optional featureor features may be present. Alternatively, the optional feature orfeatures may not be present. Ranges may be expressed herein as from oneparticular value, and/or to another particular value, which is intendedto be inclusive of the end-points of the range.

1. A method of manufacturing carboxymethylcellulose (CMC) fibrescontaining an antimicrobial, the fibres being suitable for use in thepreparation of wound dressings, wherein the antimicrobial is selectedfrom the group consisting of a biguanide, a biguanide derivative,octenidine, taurolidine, and a combination of two or more thereof, themethod comprising: submerging CMC fibres comprising at least 95 wt %carboxymethylcellulose on a dry weight basis in a treatment solution,the treatment solution comprising: a) the antimicrobial; and b) at least70 wt % of a water-miscible organic solvent selected from C₁-C₄alkanols, C₃-C₅ ketones, and a combination of two or more thereof; for aduration adequate to provide the CMC fibres containing an antimicrobial.2. The method according to claim 1, wherein the CMC fibres submerged inthe treatment solution are continuous filament fibres.
 3. (canceled) 4.The method according to claim 1 wherein the antimicrobial ispolyhexamethylene biguanide (PHMB).
 5. The method according to claim 1,wherein the treatment solution comprises from 1-10 wt % of theantimicrobial agent relative to the total weight of the solution.
 6. Themethod according to claim 1, wherein the treatment solution compriseswater in an amount of from 5-25 wt % relative to the weight of thesolution.
 7. The method according to claim 1, wherein the treatmentsolution comprises the water-miscible organic solvent in an amount offrom 70-85 wt % relative to the total weight of the solution.
 8. Themethod according to claim 1, wherein the water-miscible organic solventis selected from one or more of methanol, ethanol, propanol,isopropanol, and acetone.
 9. The method according to claim 8, whereinthe water-miscible organic solvent comprises at least 90 wt % ethanolrelative to the total weight of the water-miscible organic solvent,optionally at least 95 wt % ethanol.
 10. The method according to claim1, wherein the step of submerging in CMC fibres in the treatmentsolution is preceded by a process of forming the CMC fibres, the processof forming the CMC fibres comprising: reacting cellulose fibres with acarboxymethylating agent to provide carboxymethylcellulose (CMC) fibres.11. (canceled)
 12. The method according to claim 1, wherein the step ofsubmerging the CMC fibres in the treatment solution is preceded by astep of washing the CMC fibres with a pre-treatment wash solution.13-15. (canceled)
 16. The method according to claim 1, wherein thetreatment solution is maintained at a temperature within the range offrom 20° C. to 50° C. during the submerging step.
 17. The methodaccording to claim 1, wherein the CMC fibres are submerged in thetreatment solution for a duration of from 15 to 35 minutes.
 18. Themethod according to claim 1, wherein the step of submerging the CMCfibres is followed by washing the CMC fibres containing antimicrobialwith a post-treatment wash solution, the post-treatment wash solutioncomprising: (i) at least 98 wt % of a water-miscible organic solventselected from C₁-C₄ alkanols, C₃-C₅ ketones, and a combination of two ormore thereof; and optionally (ii) a spin finish agent, optionally from0.1-2.0 wt % spin finish agent. 19-20. (canceled)
 21. The methodaccording to claim 1, wherein the CMC fibres comprise from 0.05 to 0.8carboxymethyl groups per glucose unit as determined by potentiometrictitration. 22-26. (canceled)
 27. A carboxymethylcellulose (CMC) fibrecontaining an antimicrobial selected from a biguanide, a biguanidederivative, octenidine, taurolidine, and a combination of two or morethereof for use in the preparation of wound dressings, wherein theantimicrobial is dispersed throughout the fibre polymer. 28-29.(canceled)
 30. The CMC fibre containing an antimicrobial according toclaim 27, wherein the antimicrobial is present in the fibre in an amountof from 0.3 to 1.1 wt %, relative to the total weight of the fibre. 31.The CMC fibre containing an antimicrobial according to claim 27, whereinthe antimicrobial is polyhexamethylene biguanide (PHMB).
 32. A woven,non-woven or knitted material comprising CMC fibres containing anantimicrobial, wherein the CMC fibres containing an antimicrobial aredefined according to claim
 27. 33. (canceled)
 34. A non-woven materialcomprising entangled CMC fibres containing an antimicrobial, wherein theantimicrobial is selected from a biguanide, a biguanide derivative,octenidine, taurolidine, and a combination of two or more thereof,wherein the non-woven material exhibits a conformability characterisedby an overhang length of up to 6.5 cm in the long dimension, asdetermined by the Cantilever method described in ASTM D1388-08. 35.(canceled)
 36. A wound dressing comprising CMC fibres containing anantimicrobial, wherein the CMC fibres containing an antimicrobial are asdefined according to claim
 27. 37-38. (canceled)